Parihar R, Dierksheide J, Hu Y, Carson WEIL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells. J Clin Invest 110: 983-992

Department of Molecular Virology, Immunology, and Medical Genetics, The Arthur G. James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 11/2002; 110(7):983-92. DOI: 10.1172/JCI15950
Source: PubMed


The anti-tumor activity of recombinant mAb's directed against tumor cell growth receptors has generally been considered to result from direct antiproliferative effects, the induction of apoptosis, or possibly Ab-dependent cellular cytotoxicity mediated against tumor targets. However, it remains unclear to what degree these mechanisms actually aid in the clearance of Ab-coated tumor cells in vivo. We show here that NK cells secrete a distinct profile of potent immunostimulatory cytokines in response to dual stimulation with Ab-coated tumor cells and IL-12. This response could not be duplicated by costimulation with other ILs and was significantly enhanced in the presence of monocytes. Cytokine production was dependent upon synergistic signals mediated by the activating receptor for the Fc portion of IgG (FcgammaRIII) and the IL-12 receptor expressed on NK cells. Coadministration of Ab-coated tumor cells and IL-12 to BALB/c mice resulted in enhanced circulating levels of NK cell-derived cytokines with the capacity to augment anti-tumor immunity. These findings suggest that, in addition to mediating cellular cytotoxicity and apoptosis, the anti-tumor activity of mAb's might also result from activation of a potent cytokine secretion program within immune effectors capable of recognizing mAb-coated targets.

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    • "In this study rhIL-12 was given subcutaneously and was well tolerated but trial was terminated before completion due to low response rates in the rhIL-12 arm. More recent preclinical studies have highlighted the potential for IL-12 to costimulate NK cell IFN-γ production in combination with antitumor monoclonal antibodies [105, 113, 114]. These findings have been translated into several phase 1 and 2 clinical trials of IL-12 administered in concert with antitumor monoclonal antibodies in head and neck carcinoma [115, 116] and lymphoma [117]. "
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    ABSTRACT: Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enable NK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy.
    06/2014; DOI:10.1155/2014/205796
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    • "There is evidence supporting a role for trastuzumab in mediating ADCC [95]. The interaction between the Fc domain of trastuzumab and FcR on effecter cells has shown major ADCC involvement and IL-12 enhances cytotoxicity against mAb-coated tumor cells [96, 97]. NK cytotoxicity via ADCC is probably one of the mechanisms of action of trastuzumab, but its mode of action includes CDC and complement-dependent cell-mediated cytotoxicity [98, 99]. "
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    ABSTRACT: Natural compounds containing fungal -glucans have been used to improve general health for thousands of years in China and Japan. Lentinan, the backbone of -(1, 3)-glucan with -(1, 6) branches, is one of the active ingredients purified from Shiitake mushrooms and has been approved as a biological response modifier for the treatment of gastric cancer in Japan. Despite recent advances in chemotherapeutic agents, unresectable or recurrent gastric cancer remains an incurable disease, with survival rates being far from satisfactory. Recent clinical studies have shown that chemo-immunotherapy using lentinan prolongs the survival of patients with advanced gastric cancer, as compared to chemotherapy alone. In addition, trastuzumab, an antibody against HER2/neu growth factor receptor, has been used for the treatment of gastric cancer in combination with cytotoxic chemotherapeutic agents. Lentinan may exert a synergistic action with anti-cancer monoclonal antibodies to activate complement systems through the mechanism of antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity. Because a better understanding of its biological activities should enable us to use lentinan more efficiently in the treatment of gastric cancer, immunological effects provided by -glucans, a possible mode of action of lentinan, and its clinical application including future potential uses are discussed in the present review.
    Anti-cancer agents in medicinal chemistry 10/2012; 13(5). DOI:10.2174/1871520611313050002 · 2.47 Impact Factor
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    • "In vitro, this process is termed as ADCC. Laboratory studies have shown that HER2-overexpressing breast cancer cell lines are susceptible to ADCC in the presence of trastuzumab (Carson et al, 2001; Parihar et al, 2002; Gennari et al, 2004), and in vivo activity of trastuzumab has been correlated with significantly increased number of peritumoral lymphocytes and monocytes and in vitro ADCC (Gennari et al, 2004; Arnould et al, 2006). Additional studies have indicated that NK cells are keys for trastuzumab-mediated ADCC (Cooley et al, 1999; Clynes et al, 2000; Mimura et al, 2005). "
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    ABSTRACT: In HER2-overexpressing breast cancer, accumulating preclinical evidences suggest that some chemotherapies, like trastuzumab, but also taxanes, are able to trigger a T helper 1 (Th1) anticancer immune response that contribute to treatment success. T helper 1 immune response is characterised by the expression of the transcription factor T-bet in CD4 T lymphocytes. We hypothesised that the presence of such T cells in the tumour immune infiltrates following neoadjuvant chemotherapy would predict patient survival. In a series of 102 consecutive HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy incorporating antracyclines or taxane and trastuzumab, we studied by immunohistochemistry the peritumoral lymphoid infiltration by T-bet+ lymphocytes before and after chemotherapy in both treatment groups. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS). Fifty-eight patients have been treated with trastuzumab-taxane and 44 patients with anthracyclines-based neoadjuvant chemotherapy. The presence of T-bet+ lymphocytes in peritumoral lymphoid structures after chemotherapy was significantly more frequent in patients treated with trastuzumab-taxane (P=0.0008). After a median follow-up of 40 months, the presence of T-bet+ lymphocytes after neoadjuvant chemotherapy confers significantly better RFS (log-rank test P=0.011) only in patients treated with trastuzumab-taxane. In this population, multivariate Cox regression model showed that only the presence of T-bet+ lymphocytes in peritumoral lymphoid structures after neoadjuvant chemotherapy was independently associated with improved RFS (P=0.04). These findings indicate that the tumour infiltration by T-bet+ Th1 lymphocytes following neoadjuvant trastuzumab-taxane may represent a new independent prognostic factor of improved outcome in HER2-overexpressing breast carcinoma.
    British Journal of Cancer 07/2011; 105(3):366-71. DOI:10.1038/bjc.2011.261 · 4.84 Impact Factor
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